Diffuse Large B-Cell Non-Hodgkin Lymphoma in the Very Elderly: Challenges and Solutions

Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) is a disease of the elderly, but our current guidelines and treatment paradigms for this disease are based on studies that have mainly enrolled younger patients. Because the number of people living beyond the age of 80 increased by more than 250% between 1960 and 2000, and since it is expected that the population over the age of 75 will triple by 2030, understanding how these elderly patients should be treated is paramount to improving outcomes for this potentially curable lymphoma. In this review, we outline the scope of the problem; we define “the elderly” and identify challenges in assessing this patient population. We also summarize pivotal studies that have been conducted in these elderly patients and suggest an algorithm to aid clinicians in making treatment decisions when faced with DLBCL patients older than 80.

Introduction

Life expectancy has dramatically increased over the past 4 decades, with the number of persons over the age of 80 years increasing by more than 250% between 1960 and 2000.[1] By 2015, this age group is expected to increase by another 50%.[2] By 2030, the number of people older than 75 years will have tripled, and the subgroup of persons 85 years of age or older will have doubled in that same period.[3] Diffuse large B-cell non-Hodgkin lymphoma (DLBCL) is the most commonly diagnosed non-Hodgkin lymphoma (NHL) in Western countries. Almost one-third of newly diagnosed patients are over the age of 75.[4] While DLBCL is a potentially curable malignancy, evidence suggests that elderly patients do worse than their younger counterparts.[5] These inferior outcomes may reflect undertreatment resulting from oncologists’ perception that elderly patients are unable to tolerate aggressive therapy. Also, comorbidities that are common in the elderly might preclude the use of curative regimens that predispose some patients to life-threatening complications. In addition, DLBCL in elderly patients may be biologically and molecularly different from DLBCL in younger patients.[6] Elderly patients are more frequently diagnosed with an immunoblastic variant of DLBCL than are younger patients; this variant, which is often a marker of the ABC genotype, is known to carry a poor prognosis.[7] Also, the activated B-cell–type DLBCL and the Epstein-Barr virus (EBV)-related lymphomas are more common in elderly patients; both histologies portend a worse outcome.[8-10]

These perceptions and observations have minimized the participation of elderly patients in the clinical trials that have shaped our current therapy of DLBCL, and have raised the question of how best to treat elderly patients with DLBCL.

In this review, we critically analyze clinical trials that were specifically designed for the very elderly, and we discuss the challenges encountered by investigators who are conducting studies in this patient population. We conclude by proposing an algorithm to help clinicians determine the optimal therapeutic strategy for treatment of DLBCL in very elderly patients, defined here as those over the age of 80 years.

What is elderly?

While advanced age is considered to be an adverse prognostic factor in patients with DLBCL, the definition of “elderly” has been arbitrarily arrived at. Since the median age of newly diagnosed DLBCL patients approaches 70 years,[4] defining “elderly” as “above 60 years of age” is inadequate. The International Prognostic Index (IPI) classifies patients over age 60 as elderly, but the IPI relied on clinical trials that included very few patients over the age of 80.[11] In addition, this classification was introduced before the era of chemoimmunotherapy and prior to the significant improvement in supportive care measures. Some have defined “elderly” as the age cutoff beyond which stem-cell transplantation is contraindicated—a suboptimal definition since patients over the age of 70 with good performance status may undergo transplantation in the current era.[12,13] Furthermore, several studies have challenged the definition of “elderly” as patients over the age of 60. Advani et al compared the performance of the IPI, the age-adjusted IPI, and the revised IPI (R-IPI) against the elderly IPI (E-IPI, which uses an age cutoff of 70 years) in 267 patients older than 60 years who were treated with rituximab (Rituxan) and CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone).[14] In this small dataset, the E-IPI was more predictive of outcomes. In a German study of elderly patients with DLBCL, the investigators suggested that 75 should be the age cutoff for “elderly,” as the outcome in those older than 75 was significantly inferior to that in patients younger than 75.[15] In the absence of large prospective comparative trials, the National Comprehensive Cancer Network (NCCN) classifies elderly patients into “young old” patients (aged between 65 and 75 years); “old” patients (aged 76 to 85 years), and “oldest old” patients (aged > 85 years).[16] We propose shifting away from a definition of “elderly” based on age alone in favor of a system that comprehensively assesses each patient individually for fitness for therapy.

Challenges in Assessing and Treating the Elderly

Performance status

The Karnofsky score and the Eastern Cooperative Oncology Group (ECOG) scales have routinely been used in clinical trials to assess performance status (PS) in individual patients. While most oncologists rely on one or the other of these scales in their decision making regarding the institution of aggressive cytotoxic therapies, neither scale accounts well for comorbidities nor do they comprehensively assess patients’ functional status. Despite its limitation, PS has been incorporated in risk assessment as part of the IPI and the age-adjusted IPI.[17] Retrospective analysis of a large data set of DLBCL patients over the age of 80 demonstrated that patients’ ability to perform their activities of daily living (ADLs), as opposed to their ECOG-PS, is more predictive of overall survival (OS) and progression-free survival (PFS).[18] ADLs are basic skills that patients need to maintain their independence at home, such as the ability to bathe, dress, feed themselves, maintain continence, and avoid falls.[19] Instrumental ADLs (IADLs) assess patients’ ability to do such things as use the telephone, use transportation, go shopping, and manage finances.[20] Many patients diagnosed with malignancies have difficulties with ADLs and IADLs despite an ECOG-PS of 0, 1, or 2; however, choices of therapies have often relied on the PS as opposed to comprehensive measures of functionality.[21,22] Maione et al showed that values of the baseline quality of life (P = .0003) and the IADL score (ie, the number of IADLs for which the patient was dependent on outside help; P = .04) were associated with significantly better prognosis, whereas the ADL score (P = .44) and the Charlson Comorbidity score (Table 1 (P = .66) had no prognostic value in over 500 elderly lung cancer patients. An ECOG-PS of 2 (P = .006) and a higher number of metastatic sites (P = .02) also predicted a shorter OS.[23]

TABLE 1Charlson Weighted Comorbidity Indexa

In our opinion, deciding on a choice of therapy based on the PS without conducting a comprehensive geriatric assessment may underestimate elderly patients’ ability to tolerate treatment and might, in part, explain why they are offered less therapy. This, in turn, may deny them an opportunity for cure. The PS may complement a more comprehensive evaluation system.

Geriatric assessment

The comprehensive geriatric assessment (CGA) is a multidisciplinary evaluation of physical and psychological conditions that affect the choice of therapy for elderly patients with malignant disease. The CGA evaluates the nutritional status, cognitive skills, and comorbidities of elderly patients. Several groups have adapted CGA-based approaches in making therapeutic decisions. Examples of such decisions include omitting anthracyclines in patients with cardiac dysfunction, or omitting vincristine in those with neuropathy. Furthermore, using the CGA to help decide dose intensity and density of chemotherapy has resulted in excellent outcomes.[24] However, most studies that utilized the CGA included patients with a variety of cancers. Few trials were specifically designed for lymphoma patients. Nonetheless, these studies have shown that the domains evaluated in the CGA predict for morbidity and mortality in elderly cancer patients.[21] Incorporating the CGA into decision making would allow for the development of new endpoints in clinical trials that could specifically address quality of life and the impact of therapy on long-term physical and cognitive function. Rao et al demonstrated that elderly patients who were randomly assigned to inpatient geriatric assessment and management units experienced improved pain control and mental health scores.[25]

Tucci et al sought to determine whether the CGA could objectively identify elderly patients with DLBCL who could be effectively treated with anthracycline-based chemoimmunotherapy.[26] The CGA was performed in 84 consecutive DLBCL patients > 65 years of age who were treated with either curative or palliative intent according solely to clinical judgment. The outcomes of these patients were then analyzed according to both the treatment received and the results of the CGA. In total, 42 patients were classified as fit according to the CGA; these patients were younger (P < .0001) and had less frequent systemic symptoms (P = .03) compared with those classified as unfit by the CGA. The response rates (92.5% vs 48.8%; P < .0001) and median survival (not reached vs 8 months; P < .0001) were significantly better in the fit patients. Among the unfit patients, 20 had received curative therapy and 22 palliative therapy. The outcomes were similar irrespective of the type of treatment received (median survival, 8 vs 7 months; P < .05). Spina et al applied the CGA prospectively in a phase II study of 100 DLBCL patients over the age of 70 to assess the feasibility and efficacy of chemotherapy based on frailty.[27] Patients were divided into three groups (fit, unfit, and frail) using a modified CGA, and they then received rituximab and CHOP with dose adjustments based on comorbidities and the CGA.[27] The results support the use of the CGA as an efficient method of identifying elderly DLBCL patients who are fit enough to benefit from curative therapy and a way of sparing unfit patients unnecessary toxicities.

Because the CGA can be time-consuming, requiring up to 45 minutes to conduct for each patient,[28,29] less cumbersome assessment scales have been utilized.[24] Extermann et al assessed 24 readily available parameters in 518 patients starting chemotherapy for a variety of cancers.[30] The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score was constructed. Predictors of hematologic toxicity were the lymphocyte count, aspartate aminotransferase level, IADL score, lactate dehydrogenase (LDH) level, diastolic blood pressure, and the toxicity of the actual chemotherapy regimen. Predictors of nonhematologic toxicity were the hemoglobin level, creatinine clearance, albumin level, self-rated health, ECOG-PS score, Mini-Mental State Examination score, Mini-Nutritional Assessment score, and the toxicity of the actual chemotherapy used. The CRASH score distinguished several risk levels for severe side effects and was less time-consuming than a full CGA. However, the patients studied were heterogeneous and received various chemotherapy regimens, and few had lymphoid malignancies.[30] Hurria et al showed that incorporating the CGA, laboratory variables, tumor type, and patient and disease characteristics could predict chemotherapy toxicity in a variety of cancers for elderly patients. In this study, however, only 6% of the 500 studied patients had nonsolid tumors, and the mean age of treated patients was 73.[31] Predicting the toxicity of chemotherapy is critical in deciding which agents should be used and whether goals of therapy are safely achievable. Other scoring systems have been developed; one of the most commonly used is the Cumulative Illness Rating Scale for Geriatrics (CIRS-G).[32,33] While these scoring systems were not developed specifically for patients with lymphoma, their use in the general cancer population has provided evidence that they can affect outcomes.

In our opinion, decisions regarding treatment choice and goals in very elderly patients should rely more on these comprehensive predictive models than on the PS alone. However, prospective randomized studies in very elderly patients with DLBCL are needed to identify the most reliable system.

Comorbidities

Comorbidities are defined as chronic medical conditions that can affect a patient’s life span. Historically, the modified Charlson Comorbidity Index (see Table 1) has been used to estimate risk of mortality, based on pre-existing morbid conditions.[34] Janssen-Heijnen et al estimated that 80% of lymphoma patients older than 60 years have comorbid conditions compared with 48% of their younger counterparts.[35] The presence of comorbidities has predicted inferior OS in multivariate analyses. Several studies have demonstrated how comorbid conditions adversely affect outcomes in patients with prostate, breast, and colon cancers, and suggest that similar trends are likely to be seen in lymphoma patients.[36-38] It is also critical to evaluate the psychological state as an aspect of comorbidity, especially since older patients handle stressful illnesses poorly and their compliance is questionable.[39,40] Accordingly, routine assessment and comprehensive evaluation of comorbidity are needed prior to making a decision on the best therapeutic strategy in the very elderly.

Organ dysfunction

As patients age, organ dysfunction becomes more likely. Dysfunction may affect the kidneys, the liver, the heart, and bone marrow reserve.[41] Changes in organ function impact patients’ tolerance for therapy, pose significant challenges to the safe dosing of chemotherapeutics, and affect whether goals of care can be sustained.[42] Chemotherapy regimens that are designed to eradicate lymphomas and provide patients with an opportunity for cure might be prohibited in some patients with organ dysfunction. For example, platinum agents cannot safely be given in the presence of renal impairment. The critical administration of anthracyclines to patients with DLBCL cannot be attempted when cardiac dysfunction is present. Peripheral neuropathy could preclude administration of vincristine at full doses. Most elderly patients receive several nonchemotherapy medications to control their chronic systemic illnesses, and these may impact hepatic and renal functions.[43] Several studies have demonstrated continued decline in hematologic reserve as patients age. In fact, Marley et al showed that the decline in hematopoietic progenitor cell function may start at birth and continue throughout life.[44] If this is correct, one might expect more myelosuppression to occur in elderly patients than in younger patients in response to standard doses of chemotherapy. It is not surprising that studies have shown that advanced age is an independent risk factor for hospitalization and for the development of neutropenic fever.[45,46]